Proton Pump Inhibitors Reduce Mycophenolate Exposure in Heart Transplant Recipients—A Prospective Case-Controlled Study

Mycophenolic acid drug exposure is markedly reduced by proton pump inhibitor comedication in MMF treated transplant recipients.

This prospective study investigates the impact of proton pump inhibitors (PPI) on mycophenolic acid (MPA) pharmacokinetics in heart transplant recipients receiving mycophenolate mofetil (MMF) and tacrolimus. MPA plasma concentrations at baseline (C_{0  h}), 30 min (C_{0.5  h}), 1(C_{1  h}) and 2 h (C_{2  h}) were obtained by high-performance liquid chromatography (HPLC) in 22 patients treated with pantoprazole 40 mg and MMF 2000 mg. Measurements were repeated 1 month after pantoprazole withdrawal. A four-point limited-sampling strategy was applied to calculate the MPA area under the curve (MPA-AUC). Predose MPA concentrations with PPI were 2.6 ± 1.6 mg/L versus 3.4 ± 2.7 mg/L without PPI (p = ns). Postdose MPA concentrations were lower with PPI at C_{0.5  h} (8.3 ± 5.7 mg/L vs. 18.3 ± 11.3 mg/L, p = 0.001) and C_{1  h} (10.0 ± 5.6 mg/L vs. 15.8 ± 8.4 mg/L, p = 0.004), without significant differences at C_{2  h} (8.3 ± 6.5 mg/L vs. 7.6 ± 3.9 mg/L). The MPA-AUC was significantly lower with PPI medication (51.2 ± 26.6 mg × h/L vs. 68.7 ± 30.3 mg × h/L; p = 0.003). The maximum concentration of MPA (MPA-C_max) was lower (12.2 ± 7.5 mg/L vs. 20.6 ± 9.3 mg/L; p = 0.001) and the time to reach MPA-C_max (t_max) was longer with PPI (60.0 ± 27.8 min vs. 46.4 ± 22.2 min; p = 0.05). This is the first study to document an important drug interaction between a widely used immunosuppressive agent and a class of drugs frequently used in transplant patients. This interaction results in a decreased MMF drug exposure which may lead to patients having a higher risk for acute rejection and transplant vasculopathy.